Secretome of Mesenchymal Stromal Cells Prevents Myofibroblasts Differentiation by Transferring Fibrosis-Associated microRNAs within Extracellular Vesicles.

Publisher: MDPI Country of Publication: Switzerland NLM ID: 101600052 Publication Model: Electronic Cited Medium: Internet ISSN: 2073-4409 (Electronic) Linking ISSN: 20734409 NLM ISO Abbreviation: Cells Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI

Cell Differentiation*/drug effects ; Cell Differentiation*/genetics; Extracellular Vesicles/*metabolism ; Mesenchymal Stem Cells/*metabolism ; MicroRNAs/*metabolism ; Myofibroblasts/*metabolism ; Myofibroblasts/*pathology; Culture Media, Conditioned/pharmacology ; Extracellular Vesicles/drug effects ; Fibroblasts/drug effects ; Fibroblasts/metabolism ; Fibroblasts/pathology ; Fibrosis ; Humans ; Mesenchymal Stem Cells/drug effects ; MicroRNAs/genetics ; Myofibroblasts/drug effects ; Transforming Growth Factor beta/pharmacology

Fibroblasts differentiation into myofibroblasts is a central event of tissue fibrosis. Multipotent mesenchymal stromal cells (MSCs) secretome can interfere with fibrosis development; despite precise underlying mechanisms remain unclear. In this study, we tested the hypothesis that MSC secretome can affect fibroblast' differentiation into myofibroblasts by delivering regulatory RNAs, including microRNAs to these cells. Using the model of transforming growth factor-beta (TGFbeta)-induced fibroblast differentiation into myofibroblasts, we tested the activity of human MSC secretome components, specifically extracellular vesicles (MSC-EV). We showed that MSC-EV down-regulated secretion of extracellular matrix proteins by fibroblasts as well as suppressed their contractility resulting in prevention as well as reversion of fibroblasts differentiation to myofibroblasts. High-throughput sequencing of RNAs extracted from MSC-EV has revealed many fibrosis-associated microRNAs. Fibroblast treatment with MSC-EV led to direct transfer of microRNAs, which resulted in the elevation of most prominent fibrosis-associated microRNAs, including microRNA-21 and microRNA-29c. Using MSC-EV transfection by antagomirs to these microRNAs we demonstrated their involvement in the suppression of fibroblast differentiation in our model. Taken together, MSC secretome can suppress fibrosis by prevention of fibroblast differentiation into myofibroblasts as well as induce de-differentiation of the latter by direct transfer of specific microRNAs.

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Keywords: extracellular vesicles; fibrosis; mesenchymal stem/stromal cells; microRNA; myofibroblasts; secretome

0 (Culture Media, Conditioned)
0 (MicroRNAs)
0 (Transforming Growth Factor beta)

Date Created: 20200524 Date Completed: 20210225 Latest Revision: 20210225

20231215

PMC7290371

10.3390/cells9051272

32443855